Professor Christian Heinis at EPFL’s School of Basic Sciences has been awarded a European Research Council (ERC) Advanced Grant for a project that will merge biological and chemical compound libraries to target so-called “undruggable” proteins.
The ERC Advanced Grants are given each year to established, leading principal investigators to fund long-term funding for "ground-breaking, high-risk" research projects in three domains: Life Sciences, Physical Sciences and Engineering, and Social Sciences and Humanities.
Today, the ERC has announced the 209 winners of the 2020 Advanced Grant competition, awarded a total of €507 million. Among them is Professor Christian Heinis at the EPFL School of Basic Sciences (Institute of Chemical Sciences and Engineering). Heinis’ winning project, TARGET, aims at “developing and applying a novel method for targeting so-called ‘undruggable’ proteins by tapping into a new chemical space, generated by ‘merging’ biological and chemical compound libraries.”
“I am very grateful for the opportunity to try this bold plan and hope that my laboratory can contribute with good results to addressing currently unsolved medical challenges,” says Professor Heinis.
Full ERC press release
TARGET project description
TARGET aims at developing and applying a novel method for targeting so-called “undruggable” proteins by tapping into a new chemical space, generated by "merging" biological and chemical compound libraries. If successful, this method should deliver synthetic ligands to notoriously difficult-to-target proteins such as VEGF, KRASG12D, PCSK9, β-catenin, and MYC, for which drugs based on classical small molecules do not exist. Such ligands would offer ideal starting points for developing new therapeutics to address important unmet medical needs.
The core idea of TARGET is to merge biological and chemical compound libraries, the first library type being generated by ribosomal translation (e.g. phage-display peptide libraries) and the second one by chemical synthesis. The two types of libraries have their strengths and weaknesses and were so far used mostly independently from each other in drug development.
With biological libraries, it is possible to generate and screen more than a billion random peptides but the chemical diversity of these libraries is small (e.g. in phage-display libraries, the building blocks are mostly limited to the 20 natural amino acids). In contrast, chemical libraries are structurally highly diverse and can be generated using a nearly endless number of building blocks, but the number of molecules that can be handled and screened is limited (e.g. the Biomolecular Screening Facility BSF-ACCESS of EPFL has around 100,000 compounds in their chemical library).
In TARGET, biological compound libraries (phage-displayed peptides) will be chemically diversified with large numbers of chemical building blocks of structurally and chemically highly diverse fragments, to generate and screen a previously unseen large and structurally highly diverse chemical space.
TARGET is heavy in method development and highly interdisciplinary, using techniques ranging from DNA cloning, over chemical synthesis, to lab automation, and takes advantage of the extraordinary environment and infrastructure provided at EPFL. If successful, the project will deliver cell-permeable ligands for currently intractable targets and provide a basis for developing new drugs and addressing major diseases.